Synthesis And Cardioprotective Activity Screening Research Of Cryptotanshinone Derivatives

Cryptotanshinone is one of the main lipid-soluble components extracted from Salvia miltiorrhiza Bge.It is orange-red needle-like crystals.Pharmacological studies have shown that cryptotanshinone has anti-inflammatory,antioxidant,anticoagulant and vasodilatory properties.This paper mainly studies the synthesis of cryptotanshinone derivatives and their protective effects on cardiomyocytes,and the structure-activity relationships are preliminarily discussed.1.Synthesis of cryptotanshinone derivatives.In order to increase its polarity,water solubility and myocardial protective activity of cryptotanshinone,its structure was modified.At 120℃,with Ph Cl as the solvent and 2,2,6,6-tetramethylpiperidine-1-oxyl（TEMPO）as the electron transfer carrier,the cryptotanshinone forms the electron-deficient dihydroquinone cryptotanshinone transition state.The oxygen anions of phenol compounds attacked the electron-deficient dihydroquinone cryptotanshinone at C-1,and 48 ether derivatives were obtained,46 of which were new compounds.Comparing the yields of the products,it can be found that（1）when the substituent is an electron-donating group,the yield of the meta position is higher than that of the ortho and para positions.（2）When the substituent is an electron withdrawing group,the yield of ortho and para positions is higher.The reason may be,the position of the above substituents is more conducive to the formation and stability of phenoxy anions,thereby increasing the corresponding yield.2.Research on the protective effect of cryptotanshinone derivatives on cardiomyocytes.Normally cultured H9c2 cardiomyocytes were treated with 300μM H₂O₂to establish an oxidative stress model,and derivatives with cardioprotective activity were screened out.The results showed that compared with cryptotanshinone,most derivatives could significantly increase myocardial viability in damaged cells.Among them,DCT-01M-16 R has a significant protective effect at the concentration of 1μM and 10μM（P<0.01）;DCT-01M-13 S/R,DCT-01M-14 R,DCT-01M-15S/R,DCT-01M-16 S,DCT-01M-17 S/R,DCT-01M-21 S and DCT-01M-22 S at a concentration of 10μM,the protective effect is significant（P<0.01）;DCT-01M-12R has a significant protective effect at a concentration of 1μM（P<0.01）.The structure-activity relationship shows that,（1）The product of R configuration has better activity than that of S configuration;（2）The myocardial protection of electron-donating substituents is better than that of electron-withdrawing groups;（3）Myocardial protection of Substituent:-OCH₃>-CF₃>-NO₂,-F﹑-Cl﹑-Br and-CN have equivalent and slightly weaker protective activities.In summary,in this paper,48 cryptotanshinone ether derivatives with increased polarity have been obtained,46 of which are new compounds,and the absolute configuration of the derivatives has been determined.Experimental results of cardiomyocyte oxidative stress model show that compared with cryptotanshinone,most of the compounds have improved cardioprotective activity.The results of the study provide a reference for the further structural modification of cryptotanshinone derivatives,as well as the development and utilization of tanshinone compounds in the field of cardiovascular therapy.